The present invention provides a noninvasive, quantitative test for prognosis determination in cancer patients. The test relies on measurements of the tumor levels of certain messenger RNAs (mRNAs). These mRNA levels are inserted into a polynomial formula (algorithm) that yields a numerical recurrence score, which indicates recurrence risk.
Legal claims defining the scope of protection, as filed with the USPTO.
1. A method for determining the likelihood of breast cancer recurrence or response to hormonal therapy in a human subject comprising: (a) measuring the expression levels of the RNA transcripts of SURV, Ki.67, MYBL2, CCNB1, STK15, CTSL2, and STMY3, or their expression products, in a biological sample containing tumor cells obtained from said subject; (b) calculating a recurrence score (RS) for said subject by weighting the measured expression levels of gene subsets by contribution to breast cancer recurrence, wherein the gene subsets comprise: (i) a proliferation subset: SURV, Ki.67, MYBL2, CCNB1, and STK15; and (ii) an invasion subset: CTSL2, and STMY3; and (c) creating a report providing the RS; wherein the RS is indicative of the likelihood of breast cancer recurrence in said subject or response of said subject to hormonal therapy.
2. The method of claim 1 , wherein the expression of the genes SURV, K167, MYBL2, CCNB1, STK15, CTSL2, and STMY3 is measured by determining protein expression levels.
3. The method of claim 1 , further comprising measuring the expression levels of RNA transcripts of CD68, GSTM1 and BAG1 or their expression products, or corresponding substitute genes or their expression products, and including the contribution of the measured expression levels of the genes or substitute genes to breast cancer recurrence in calculating the RS, wherein a higher RS represents an increased likelihood of breast cancer recurrence, and wherein a corresponding substitute gene for CD68 is selected from the group consisting of CTSB, CD18, CTSL, HLA.DPB1, and MMP9, a corresponding substitute gene for GSTM1 is selected from the group consisting of GSTM2, GSTM3, GSTM4, GSTM5, MYH11, GSN, and ID1, and a corresponding substitute gene for BAG1 is selected from the group consisting of Bcl2, GATA3, DHPS, and HNF3A.
4. The method of claim 3 , wherein the expression of the genes SURV, K167, MYBL2, CCNB1, STK15, CTSL2, STMY3, CD68, GSTM1, and BAG1 is measured by determining protein expression levels.
5. The method of claim 1 , wherein the cancer is lymph node negative breast cancer.
6. The method of claim 1 , wherein the individual contribution of each gene of gene subsets (i) and (ii) is weighted separately.
7. The method of claim 1 , comprising weighting equally the individual contributions of the genes listed in gene subset (i), or their expression products, to breast cancer recurrence.
8. The method of claim 1 , comprising weighting equally the individual contributions of the genes listed in gene subset (ii), or their expression products, to breast cancer recurrence.
9. The method of claim 1 , wherein increased levels of the RNA transcripts of the genes in gene subsets (i) and (ii), or their expression products, are associated with increased risk of breast cancer recurrence, and are assigned a positive value.
10. The method of claim 3 , wherein increased level of the RNA transcript of CD68, or its expression product, is associated with increased risk of breast cancer recurrence, and is assigned a positive value.
11. The method of claim 3 , wherein increased levels of the RNA transcripts of GSTM1 and BAG1, or their expression products, are associated with decreased risk of breast cancer recurrence, and are assigned a negative value.
12. The method of claim 1 , wherein said biological sample is selected from the group consisting of fresh tumor tissue, fine needle aspirates, peritoneal fluid, ductal lavage and pleural fluid.
13. The method of claim 1 , wherein said biological sample is obtained from a fixed, paraffin embedded tumor tissue.
14. The method of claim 13 , wherein said tissue has been obtained by biopsy.
15. The method of claim 1 , wherein the expression levels of said RNA transcripts are determined by reverse transcription-polymerase chain reaction.
16. The method of claim 1 , wherein said RNA is fragmented.
17. A method for determining a likelihood of breast cancer recurrence or response to hormonal therapy in a human subject comprising: a. measuring expression levels of RNA transcripts for a plurality of genes, or their expression products, in a biological sample containing tumor cells obtained from the subject, wherein the plurality of genes are grouped in gene subsets comprising: (i) SURV, Ki.67, MYBL2, CCNB1, and STK15; and (ii) CTSL2, and STMY3, wherein at least one gene within subset (i) may be replaced by a substitute gene from a group consisting of C20.orfl, TOP2A, CDC20, KNSL2, MELK, TK1, NEK2, LMNB1, PTTG1, BUB1, CCNE2, F1120354, MCM2, RAD54L, PRO2000, PCNA, Chk1, NME1, TS, FOXM1, AD024, and HNRPAB, b. calculating a recurrence score (RS) for the subject by weighting of the measured expression levels for each of the gene subsets by contribution to breast cancer recurrence; and c. creating a report which includes the RS; wherein the RS is indicative of a likelihood of breast cancer recurrence or response to therapy in said human subject.
18. The method of claim 17 , further comprising measuring expression levels of RNA transcripts of CD68, GSTM1 and BAG1, or a substitute gene thereof, or their expression products, and including the contribution of measured expression levels of CD68, GSTM1 and BAG1, or substitute genes, to breast cancer recurrence in calculating the RS, wherein a higher RS represents an increased likelihood of breast cancer recurrence, wherein a substitute gene for CD68 is selected from the group consisting of CTSB, CD18, CTSL, HLA.DPB1, and MMP9, wherein a substitute gene for GSTM1 is selected from the group consisting of GSTM2, GSTM3, GSTM4, GSTM5, MYH11, GSN, and ID1, and wherein a substitute gene for BAG1 is selected from the group consisting of Bcl2, GATA3, DHPS, and HNF3A.
19. The method of claim 18 , wherein an increased level of a RNA transcript of CD68 or a substitute gene, or its expression product, is associated with an increased risk of breast cancer recurrence, and is assigned a positive value.
20. The method of claim 18 , wherein increased levels of RNA transcripts of GSTM1 and BAG1, or a substitute gene thereof, or their expression products, are associated with a decreased risk of breast cancer recurrence, and are assigned a negative value.
21. The method of claim 17 , wherein the cancer is lymph node negative breast cancer.
22. The method of claim 17 , wherein the contributions of gene subset (i) is included at a threshold value until the contributions exceed the threshold value, at which point the contributions are included as a total expression level of the RNA transcripts of the genes or substitute genes in said subsets, or their expression products.
23. The method of claim 17 , wherein, within each of gene subset (ii), individual contributions of each gene or substitute gene included is weighted separately.
24. The method of claim 17 , comprising weighting equally individual contributions of the genes or substitute genes of gene subset (i), or their expression products, to breast cancer recurrence.
25. The method of claim 17 , comprising weighting equally individual contributions of each gene or substitute gene of gene subset (ii), or their expression products, to breast cancer recurrence.
26. The method of claim 17 , wherein increased levels of RNA transcripts of the genes or substitute genes of gene subsets (i) and (ii), or their expression products, are associated with increased risk of breast cancer recurrence, and are assigned a positive value.
27. The method of claim 17 , wherein the contributions of gene subset (i) is included at a threshold value until the contributions exceed the threshold value, at which point the contributions are included as a total expression level of the RNA transcripts of the genes in said subsets, or their expression products.
28. The method of claim 18 , wherein the expression of the genes SURV, K167, MYBL2, CCNB1, STK15, CTSL2, STMY3, CD68, GSTM1, and BAG1 is measured by determining protein expression levels.
29. The method of claim 17 , wherein the expression levels of said RNA transcripts are determined by reverse transcription-polymerase chain reaction.
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March 18, 2009
May 10, 2011
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